The Role of IL-6 Trans-Signaling in Vascular Leakage: Implications for Ovarian Hyperstimulation Syndrome in a Murine Model

Journal of Clinical Endocrinology and Metabolism

CONTEXT
The inflammatory cytokine IL-6 is related to ovarian hyperstimulation syndrome (OHSS), although the functional role of IL-6 in OHSS remains largely unknown.

OBJECTIVE
A key feature of the IL-6 response is that its regulation is dependent on IL-6 trans-signaling via soluble IL-6 receptor-a (sIL-6Ra). The objective of the study was to elucidate the mechanistic role of IL-6trans-signaling in the vascular leakage that underlies the pathophysiology of OHSS.

DESIGN
Ovarian endothelial cells (ECs) and granulosa-lutein cells were obtained from women undergoing in vitro fertilization. OHSS was induced in mice by administering gonadotropins for 2 days followed by human chorionic gonadotropin. The functional role of IL-6 trans-signaling in OHSS was verified using the designer cytokines Hyper IL-6 and sgp130-Fc.

RESULTS
The follicular fluid levels of sIL-6Ra were elevated in women at high risk for OHSS. In the murine OHSS model, stimulation with gonadotropins significantly induces ovarian IL-6 and sIL-6Ra expression. In vitro, FSH induces de novo sIL-6Ra synthesis in granulosa-lutein cells through a protein kinase C-dependent pathway. In addition, sIL-6Ra was released by leukocytes in the presence of conditioned medium from human chorionic gonadotropin-treated granulosa-lutein cells. Ovarian ECs responded to the IL-6Ra–IL-6 complex (Hyper IL-6) but not to IL-6 alone. With activation of signal transducer and activator of transcription 3 (STAT3) and ERK, Hyper IL-6 increased vascular endothelial growth factor expression and the vascular permeability of ECs. Selective blockade of IL-6 trans-signaling by sgp130-Fc significantly inhibited vascular endothelial growth factor expression and prevented OHSS in mice.

CONCLUSIONS
IL-6 trans-signaling is activated during the ovarian stimulation process. Our findings provide insight into the biologic effects of IL-6 trans-signaling in OHSS and highlight that IL-6 trans-signaling can induce vascular leakage in this disease.